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Safety Assessment of 4'-Thio-β-D-Arabinofuranosylcytosine in the Beagle Dog Suggests a Drug-Induced Centrally Mediated Effect on the Hypothalamic-Pituitary-Adrenal Axis

OSI Pharmaceuticals, Inc., Boulder, Colorado, USA

Correspondence: Address correspondence to Daniel W. Drolet, OSI Pharmaceuticals, Inc., 2860 Wilderness Place, Boulder, CO 80301, USA. E-mail:ddrolet{at}osip.com

4'-Thio-β-D-arabinofuranosylcytosine (OSI-7836) is a nucleoside analogue with structural similarity to gemcitabine and cytarabine (ara-C). Myelosuppression, reversible transaminase elevations, and flu-like symptoms are common side effects associated with human use of gemcitabine and ara-C. Fatigue is also associated with the use of gemcitabine and OSI-7836 in humans. To better understand the toxicity of OSI-7836, subchronic studies were conducted in dogs. OSI-7836 was administered on days 1 and 8 or on days 1, 2, and 3 of a 21-day dose regimen. These schedules attempted to match clinical trial dosing regimens. Routine toxicity study end points demonstrated that OSI-7836 was primarily cytotoxic to the gastrointestinal tract, bone marrow, and testes; the myelotoxicity was mild and reversible. Plasma pharmacokinetics were dose-linear with an elimination half-life of 2.2 h. Follow-up single dose experiments in dogs assessed drug effects on lymphocyte subpopulations and on adrenal and thyroid function. Populations of T and B cells were equally reduced following OSI-7836 administration. There were no adverse effects on thyroid function, but there were marked reductions in circulating cortisol and adrenocorticotropic hormone concentrations suggesting a centrally mediated impairment of the hypothalamic-pituitary-adrenal axis. These findings show a toxicological profile with OSI-7836 similar to other nucleoside analogues and suggest that the beagle is a model for studying one possible cause of OSI-7836-related fatigue, impaired function of the hypothalamic-pituitary-adrenal axis.

Key Words: ACTH Stimulation • Beagle Dog • Fatigue • Nucleoside Analogue • Safety Assessment

International Journal of Toxicology, Vol. 25, No. 2, 119-126 (2006)
DOI: 10.1080/10915810600605898


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